Neuropeptide Y and Y2-receptor are involved in development of diabetic retinopathy and retinal neovascularization

BACKGROUND: Neuropeptide Y is a sympathetic neurotransmitter, a potent endothelium-derived angiogenic factor and a vascular mitogen. We have studied the role of the functional leucine7 to proline7 polymorphism of the signal peptide region of preproneuropeptide Y (prepro-NPY) as a genetic susceptibility factor for diabetic retinopathy. In addition, we investigated the role of the NPY Y2-receptor as a putative mediator of angiogenic NPY signaling in the retina. METHODS: Frequencies of proline7 (Pro7) carriers in the prepro-NPY were determined in type 1 and type 2 diabetes patients having retinopathy, in type 2 diabetes patients without retinopathy and in healthy control subjects. The role of Y2-receptor in hyperoxemia-induced retinal neovascularization was investigated in Y2-receptor knockout mice (Y2-/-) and in rats administered Y2-receptor mRNA antisense oligonucleotide. RESULTS: The carriers having Pro7 in the preproNPY are markedly over-represented among type 2 diabetes patients with retinopathy compared to type 2 diabetes patients without retinopathy and to the population control. Neonatal exposure to hyperoxia resulted in development of retinal neovascularization that was prevented in Y2(-1-) -mice, and significantly inhibited in rats treated with the Y2-receptor antisense oligonucleotide. CONCLUSIONS: NPY and Y2-receptor play important roles in diabetic retinopathy and retinal neovascularization and are thus potential new targets for drug molecules for treatment of retinopathy.     

Asymptomatic visual field disturbances in multiple sclerosis patients without a history of optic neuritis

BACKGROUND AND PURPOSE: The aim of our study was to evaluate visual field in patients with multiple sclerosis without a history of optic neuritis. We assessed presence and localisation of visual field defects and evaluated correlation between visual field disturbances and patient's neurological status. MATERIAL AND METHODS: A group of 52 patients with multiple sclerosis and 17 healthy persons who served as the control group were enrolled into the study. The patients went through a routine neurological examination, ophthalmologic check-up and perimetric visual field assessment. Visual fields were examined with static perimetry Medmont M700. In all of the patients, results of perimetry were evaluated according to localisation of lesions. A decibel scale was used to quantitatively assess disturbances in patient's visual field. RESULTS: We found that "asymptomatic" visual field disturbances were present in a large number (38, 73.1%) of multiple sclerosis patients. Among these patients, we diagnosed concentric visual field lesions in 46.2%, and we recognized disturbances in the upper part of the visual field in 26.9%. There was a correlation between the presence of those visual field lesions, duration of multiple sclerosis, and the degree of patients' disability. CONCLUSIONS: Asymptomatic visual field disturbances occur frequently in MS patients (despite no history of retrobulbar optic neuritis). Static perimetry may be a valuable, complementary method in addition to examinations used so far in the diagnosis of multiple sclerosis.     

Hypomorphic mutation of ZAP70 in human results in a late onset immunodeficiency and no autoimmunity

Complete lack of function of the tyrosine kinase ZAP70 in humans results in a severe immunodeficiency, characterized by a lack of mature CD8⁺ T cells and non‐functional CD4⁺ T cells. We report herein an immunodeficiency with an inherited hypomorphic mutation of ZAP70 due to a single G‐to‐A substitution in a non‐coding intron. This mutation introduces a new acceptor splice site and allows low levels of normal alternative splicing and of WT ZAP70 expression. This partial deficiency results in a compromised TCR signaling that was totally restored by increased expression of ZAP70, demonstrating that defective activation of the patient T cells was indeed caused by the low level of ZAP70 expression. This partial ZAP70 deficiency was associated with an attenuated clinical and immunological phenotype as compared with complete ZAP70 deficiency. CD4⁺ helper T‐cell populations including, follicular helper T cells, Th1, Th17 and Treg were detected in the blood. Finally, the patient had no manifestation of autoimmunity suggesting that the T‐cell tolerogenic functions were not compromised, in contrast to what has been observed in mice carrying hypomorphic mutations of Zap70. This report extends the phenotype spectrum of ZAP70 deficiency with a residual function of ZAP70.     

Concomitant administration of fluoxetine and amantadine modulates the activity of peritoneal macrophages of rats subjected to a forced swimming test

Recent studies show that administration of a non-competitive NMDA receptor antagonist, amantadine (AMA), potentiates the action of antidepressant drugs. Since antidepressants may modulate functioning of the immune system and activation of a pro-inflammatory response in depressive disorders is frequently reported, the aim of the present study was to examine whether a combined administration of AMA and the antidepressant, fluoxetine (FLU), to rats subsequently subjected to a forced swimming test (FST) modifies the parameters of macrophage activity, directly related to their immunomodulatory functions, i.e., arginase (ARG) activity and synthesis of nitric oxide (NO). We found that 10 mg/kg AMA and 10 mg/kg FLU, ineffective in FST for antidepressant-like activity when administered alone, increased the ARG/NO ratio in macrophages when administered concomitantly. This effect was accompanied by a decrease of cellular adherence. Concurrently, the basal metabolic activity of the cells measured with reduction of resazurin, and intracellular host defense as assessed by a synthesis of superoxide anion, were not affected by such antidepressive treatment. Our data indicate that co-administration of AMAand FLU decreases the pro-inflammatory properties of macrophages and causes a redirection of immune response toward anti-inflammatory activity, as one can anticipate in the case of an effective antidepressive treatment.     

Nuclear architecture remodelling in cardiomyocytes with lamin A deficiency

We analysed the architecture of cardiomyocyte nuclei lacking lamin A activity in three patients with dilated cardiomyopathy. The diagnosis was established on the basis of clinical and electrophysiological examinations, chest radiography and electrocardiography. An ultrastructural study of affected cardiomyocytes showed dramatic alterations in nuclear distribution and organization affecting nuclear shape, lamina structure, chromatin and nuclear interior organization. The most specific hallmark of nuclei with lamin A deficiency was the reorganization of the nuclear interior, the appearance of a various number of mitochondria within the nuclear matrix, and focal or total lack of nuclear membrane.     

What do tachycardiomyopathy belong to?: reply

We thank Dr Pieroni and colleagues for their response to theposition statement from the